ANN ARBOR, MI – Millions of Americans hear ringing in their ears — a condition called tinnitus — but a new study shows an experimental device could help quiet the phantom sounds by targeting unruly nerve activity in the brain.
In a new paper in Science Translational Medicine, a team from the University of Michigan reports the results of the first animal tests and clinical trial of the approach, including data from 20 human tinnitus patients.
Based on years of scientific research into the root causes of the condition, the device uses precisely timed sounds and weak electrical pulses that activate touch-sensitive nerves, both aimed at steering damaged nerve cells back to normal activity.
Human participants reported that after four weeks of daily use of the device, the loudness of phantom sounds decreased, and their tinnitus-related quality of life improved. A sham “treatment” using just sounds did not produce such effects.
Results from tests in guinea pigs and the double-blind human study funded by the Coulter Foundation validate years of pre-clinical research funded by the National Institutes of Health, including previous tests in guinea pigs.
The U-M team has new NIH funding for an additional clinical trial to further refine the approach. U-M holds a patent on the concept behind the device and is developing it for potential commercialization.
“The brain, and specifically the region of the brainstem called the dorsal cochlear nucleus, is the root of tinnitus,” says Susan Shore, Ph.D., the U-M Medical School professor who leads the research team. “When the main neurons in this region, called fusiform cells, become hyperactive and synchronize with one another, the phantom signal is transmitted into other centers where perception occurs.
“If we can stop these signals, we can stop tinnitus,” she continues. “That is what our approach attempts to do, and we’re encouraged by these initial parallel results in animals and humans.”
A dual-stimulus approach to treating tinnitus
The approach, called targeted bimodal auditory-somatosensory stimulation, involves two senses. The device plays a sound into the ears, alternating it with precisely timed, mild electrical pulses delivered to the cheek or neck.
This sets off a process called stimulus-timing dependent plasticity, or STDP, which was first explored in animals and led to long-term changes in the rate at which the nerves fire. The approach aims to re-set the activity of fusiform cells, which normally help our brains receive and process both sounds and sensations such as touch or vibration – what scientists call somatosensory inputs.
Under normal conditions, fusiform cells help our brains focus on where sounds are coming from, and help us tune out sensations that result from the movement of our own head and neck.
But the U-M team’s previous work in animals showed that loud noise can trigger a change in the nerve cells’ activity – altering its timing so that they fire off synchronized signals spontaneously instead of waiting for an actual sound in the environment.
The toll of tinnitus
These events in animals parallel what happens in humans. After exposure to such things as loud noises, head or neck trauma, or other triggering events, some people develop a persistent sensation that they’re hearing sounds like ringing or a grinding noise.
Approximately 15 percent of Americans have some level of tinnitus, but the worst symptoms occur in about 10 percent of sufferers, according to estimates based on interviews with nationally representative samples of Americans. Many of those with more severe tinnitus also have hearing loss.
Some cases are severe. As many as two million people can’t work or carry out other daily activities because of the tinnitus itself, or the psychological distress it causes them. Tinnitus is the most common cause of service-connected disability among veterans of the U.S. military.
Current approaches to tinnitus treatment focus include efforts to address the psychological distress it causes, for instance through cognitive behavioral therapy. Other approaches use sound to mask the phantom sounds or attempt to modulate the brain response. For more severe cases, some patients turn to invasive, and therefore riskier, approaches such as deep brain stimulation and vagal nerve stimulation. The current approach provides a novel and unique, non-invasive strategy that aims to modulate and correct the aberrant neural pathways that cause tinnitus.
Shore and her colleagues are based in U-M’s Kresge Hearing Research Institute, which is part of the Department of Otolaryngology at Michigan Medicine, U-M’s academic medical center. Co-first authors Kendra Marks, Au.D., David Martel, M.S.E. and Calvin Wu, Ph.D., are all members of the Shore laboratory.
They recruited a particular kind of tinnitus sufferer for their study: those who can temporarily alter their symptoms if they clench their jaws, stick out their tongues, or turn or flex their necks. These maneuvers, Shore says, appear to be self-discovered ways of changing the activity of fusiform cells – providing an external somatosensory signal to modulate their tinnitus.
The U-M device delivers sounds matched to the loudness and pitch of the phantom sounds that each patient hears. It also delivers mild electrical impulses applied to the area of the head involved in the patients’ own tinnitus-altering maneuvers.
The crucial timing of the auditory and electrical stimulation came directly from tests in guinea pigs that had noise-induced tinnitus, reported in the new paper. Those tests showed that specific timing between delivery of the two kinds of stimuli was necessary to suppress the hyperactive fusiform cells.
After patients had the device calibrated to their own tinnitus symptoms, they learned to apply its earphones and electrodes for a 30-minute session each day. Half the group received the bimodal sound-and-electricity treatment for the first four weeks, while the other half received just sounds. Then, they all took a four-week break, and started the next four weeks receiving the opposite of what they’d received before. None of them knew which option they got first.
Every week, the patients took a survey about how much their tinnitus was affecting their lives, and a test of how loud their tinnitus sounds were.
Results in human participants
Overall, the loudness of phantom sounds decreased only after the actual, or bimodal, treatment, but not the sham treatment of sound only. For some the decrease was around 12 decibels, about the magnitude of an electric lightbulb’s hum. Two participants said their tinnitus disappeared completely.
The quality of life survey – where a low score indicates less impact from tinnitus – is called TFI, and is measured on a 100-point scale. Statistical modeling of the results revealed that, on average, patients experienced significantly reduced scores for the active treatment, though the size of the effect in individual patients varied. On average, scores also stayed lower for weeks after treatment ended. This effect was not significant for the sham treatment.
No patient experienced a worsening of symptoms or quality of life, or other adverse events. Some said their phantom sounds got less harsh or piercing, or became easier to ignore.
“We’re definitely encouraged by these results, but we need to optimize the length of treatments, identify which subgroups of patients may benefit most, and determine if this approach works in patients who have non-somatic forms of the condition that can’t be modulated by head and neck maneuvers,” says Shore.
The research was funded by NIH grants DC004825 and DC00011, and by the Wallace H. Coulter Translational Research Partnership. The device was built at in2being LLC based on patent 9,242,067 granted to U-M in 2016. The device is experimental and not commercially available; potential cost of treatment has yet to be determined.
More information on the design of the clinical trial is available at https:/
Recruitment for the next clinical trial will begin in early 2018, with the trial expected to start in late summer. Information will be posted on http://www.
In addition to Shore, Marks, Martel and Wu, the study’s authors are U-M assistant professor of otolaryngology Gregory Basura, M.D., Ph.D.; U-M assistant professor of otolaryngology, Kara Schvartz-Leyzac, Au.D., Ph.D. and Larry Roberts, Ph.D., Professor emeritus of McMaster University in Canada. Reference: Science Translational Medicine, 10, eaal3175
Millions of Americans suffer from a medical condition known as tinnitus, a disorder so tormenting that it makes Edgar Allen Poe’s talking, taunting raven sound charming. People with tinnitus are plagued by phantom noises, usually ringing or buzzing, sometimes to the point where they can no longer work or function. Worse still, cases are often chronic and incurable: Current treatments include cognitive behavioral therapy to help people manage the distress it causes, using actual sounds to mask the ringing, or invasive brain surgery that often doesn’t work. But the findings of a new study, published today in Science Translational Medicine, seem to offer something much more promising—a noninvasive treatment that attacks the root source of tinnitus while making life noticeably easier for its sufferers.
Researchers at the University of Michigan believe they’ve figured out how to short-circuit the complex neurological process that results in tinnitus
One of the leading theories behind what causes most cases of chronic tinnitus is that it begins with misfiring neurons in the dorsal cochlear nucleus—one of the two regions of the brainstem where auditory information is first processed. These neurons, called fusiform cells, are meant to fire when the brain receives input from the outside world, which is one of the first links in an almost simultaneous chain of events that leads to us correctly “hearing” the sound something makes. In people with tinnitus, this synchrony is thrown off-kilter and the fusiform cells fire whenever they please, leading to people hearing sounds that aren’t there. This initial imbalance can be caused by anything from damaging loud noises to ear infections, it’s thought, and often accompanies hearing loss.
The University of Michigan team, based on research they had done with guinea pigs, created (and patented) a device they think can retrain the brain circuitry involved in causing at least some cases of tinnitus.
“We worked out in animal studies that specific combinations of sound and pulses could either increase or decrease the activity of these [fusiform] cells that activate the rest of the brain,” senior author Susan Shore of the university’s Kresge Hearing Research Institute told me in an email. So their device, via headphones and electrodes placed on the person’s neck and head, sends out bursts of sounds and mild electrical pulses that alternate with one another. This theoretically resets the fusiform cells and decreases how often and severely a person’s tinnitus should happen.
After successful animal experiments, the researchers recruited 20 volunteers with tinnitus to take part in a 16-week experiment where they would take home and use a device every day. Half of the volunteers used the sounds-and-shocks device daily for four weeks, took a four-week break, and then used a similar device that only emitted sounds, but no shocks, for another four weeks, and finally took another four-week break. The other half did the same schedule of four weeks on followed by four weeks off, but they instead started with the sounds-only device, and then moved on to the sounds-and-shocks device.
During the weeks the volunteers were using the real device (the one that emitted both sounds and shocks), they reported less noisy and high-pitched episodes of tinnitus along with fewer episodes overall—two even said their tinnitus went fully away. That predictably led to a better quality of life and reduced stress for the volunteers.
Wonderful as a noninvasive and practically risk-free device (unless you can’t stand mild shocks) to treat tinnitus could be, it might not come without its limitations. The subjects’ tinnitus largely returned a week after they stopped using the device, even for the two people who reported losing it completely. The researchers also only used volunteers with a particular form of tinnitus. These sufferers are able to soften their episodes by applying pressure to their head or clenching their jaw—a rudimentary version of keeping their fusiform cells in check, it’s thought. That could mean the device won’t work for the 20 percent to 40 percent of tinnitus sufferers without that particular quirk.
The device’s effects did seem to accumulate the more it was used, Shore said, suggesting that a longer course could provide longer-term relief. “This treatment is only 30 minutes a day, so even if people had to use it every day or once a week, it would be helpful,” she added.
The team next plans to test out their device with a much larger group of people. This new study is already recruiting volunteers and is set to start in April. Researchers elsewhere are exploring a similar “bi-modal stimulation” approach to treating tinnitus. If this work continues to pay off, these devices could be a game-changer. It’s estimated that at least 15 percent of Americans, or 50 million people, suffer from tinnitus, while two million have a severe or debilitating case of it.
“Cosine window-gated tone signals (50 ms duration, 2 ms rise/fall time) were generated using Open Ex and an RX8 DSP (TDT) with 12 bit precision and sampling frequency set at 100 kHz. A shielded speaker (DT770, Beyer) driven by an HB7 amplifier (TDT) delivered sound through a hollow earbar to the left year. The system response was measured with a condenser microphone attached to the hollow earbar by a ¼” long tube approximating the ear canal. Sound levels were adjusted to account for the system response using a programmable attenuator (PA5, TDT) to deliver calibrated levels (dB SPL) at frequencies from 200 Hz to 24 kHz. Neurons in somatosensory brainstem nuclei (Sp5) known to project to DCN were activated by three biphasic (100 μs/phase) current pulses at 1000 Hz delivered to Sp5 through a concentric bipolar electrode (Shore et al., 2008). Responses to unimodal Sp5 stimulation were assessed before any bimodal stimulation and classified as excitatory, inhibitory, or having a complex excitatory/inhibitory pattern. The current amplitude was set to the highest level (range 50–70 μA) that did not elicit movement artifact.”